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Background: Proton minibeam radiation therapy (pMBRT) can deliver spatially fractionated dose distributions with submillimeter resolution. These dose distributions exhibit significant heterogeneity in both depth and lateral directions. Accurate characterization of pMBRT doses requires dosimetry devices with high spatial resolution and a wide dynamic range. Furthermore, the dependency of dosimetric measurements on Linear Energy Transfer (LET), as observed in conventional proton therapy, is also present in pMBRT depth dose measurements. Purpose: This work demonstrates the process of performing comprehensive dosimetric measurements to characterize the pMBRT collimator on a clinical single-gantry proton machine, utilizing commercially available dosimetry devices. Methods: The minibeam collimator is designed to be mounted on the clinical nozzle as a beam-modifying accessory. Three collimators, each with a slit opening of 0.4 mm, are thoroughly evaluated. The center-to-center (c-t-c) distances of the slits for these collimators are 2.8 mm, 3.2 mm, and 4.0 mm, respectively. High spatial resolution dosimetry devices are essential for PMBRT dose characterizations. To meet this requirement, two-dimensional (2D) dose measurement devices, Gafchromic films, are used to measure lateral profiles at various depths. Films are also used for depth dose profile measurements in solid water. Additionally, high-resolution point dose detectors, microDiamond, and Razor diode detectors are employed for lateral profile measurements at various depths. Percent depth dose (PDD) measurements of pMBRT in solid water, with various proton energies, collimators, and air gaps, are performed using Gafchromic films. The film's LET dependency for proton beams is corrected to ensure accurate pMBRT PDD measurements. The Monte Carlo simulation tool TOPAS is utilized to compare and validate all experimental measurements. Results: At depths where LET is not a concern, film dose measurements were consistent with microDiamond and Razor diode point measurements. The point detectors need to be orientated with the thin side aligned to the incoming beam. Comparison of the lateral dose profiles extracted from TOPAS simulations, films, microDiamond, and Razor diode detectors shows a passing rate exceeding 98% in 1D gamma analysis at 3% 0.1 mm criteria.However, when the microDiamond detector is orientated to face the pMBRT beam, its spatial resolution may not be sufficient to capture the peak and valley dose accurately. Nevertheless, an accuracy within 2% can still be achieved when comparing the average dose. The PDD measurements show that the peak valley dose ratio (PVDR) of pMBRT can be altered at different depths with different air gaps using the same collimator or different collimators of different c-t-c distances. Conclusion: Our study demonstrates that comprehensive dose measurements for pMBRT can be conducted using standard clinical dose measurement devices. These measurements are indispensable for guiding and ensuring accurate dose reporting in pre-clinical studies using the pMBRT technique.
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BACKGROUND: Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV). PURPOSE: This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED. METHODS: SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method. RESULTS: SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26 Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10 mm ring expansion of CTV). CONCLUSION: We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO.
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Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Planejamento da Radioterapia Assistida por Computador/métodos , Doses de Radiação , Humanos , Órgãos em Risco/efeitos da radiação , Terapia com Prótons/métodos , Modelos BiológicosRESUMO
BACKGROUND: Minibeam represents a preclinical spatially fractionated radiotherapy modality with great translational potential. The advantage lies in its high therapeutic index (compared to GRID and LATTICE) and ability to treat at greater depth (compared to microbeam). Proton minibeam radiotherapy (pMBRT) is a synergy of proton and minibeam. While the single-gantry proton facility has gained popularity due to its affordability and compact design, it often has limited beam time available for research purposes. Conversely, given the current requirement of pMBRT on specific minibeam hardware collimators, necessitates a reproducible and fast setup to minimize pMBRT treatment time and streamline the switching time between pMBRT and conventional treatment for clinically translation. PURPOSE: The contribution of this work is the development and characterization of the first pMBRT system tailored for single-gantry proton facility. The system allows for efficient and reproducible plug-and-play setup, achievable within minutes. METHODS: The single room pMBRT system is constructed based on IBA ProteusONE proton machine. The end of nozzle is attached with beam modifying accessories though an accessory drawer. A small snout is attached to the accessory drawer and used to hold apertures and range shifters. The minibeam aperture consists of two components: a fitting ring and an aperture body. Three minibeam apertures were manufactured. The first-generation apertures underwent qualitatively analysis with film, and the second generation aperture underwent more comprehensive quantitative measurement. The reproducibility of the setup is accessed, and the film measurements are performed to characterize the pMBRT system in cross validation with Monte Carlo (MC) simulations. RESULTS: We presented initial results of large field pMBRT aperture and the film measurements indicates the effect of source-to-isocenter distance = 930 cm in Y proton scanning direction. Consistent with TOPAS MC simulation, the dose uniformity of pMBRT field <2 cm is demonstrated to be better than 2%, rendering its suitability for pre-clinical studies. Subsequently, we developed the second generation of aperture with five slits and characterized the aperture with film dosimetry studies and compared the results to the benchmark MC. Comprehensive film measurements were also performed to evaluate the effect of divergence, air gap and gantry-angle dependency and repeatability and revealing a consistent performance within 5%. Furthermore, the 2D gamma analysis indicated a passing rate exceeding 99% using 3% dose difference and 0.2 mm distance agreement criteria. We also establish the peak valley dose ratio and the depth dose profile measurements, and the results are within 10% from MC simulation. CONCLUSIONS: We have developed the first pMBRT system tailored for a single-gantry proton facility, which has demonstrated accuracy in benchmark with MC simulations, and allows for efficient plug-and-play setup, emphasizing efficiency.
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Desenho de Equipamento , Terapia com Prótons , Terapia com Prótons/instrumentação , Método de Monte Carlo , Prótons , Dosagem RadioterapêuticaRESUMO
Head and neck cancer (HNC) is a challenging disease that lacks effective treatment, particularly in the cases that spread locoregionally and metastasize distantly, dramatically reducing patient survival rates. Expanding the understanding of the mechanisms of the metastatic cascade is critical for creating more effective therapeutics that improve outcomes for HNC patients. A true grasp of cancer metastasis requires the consideration of all cell types that contribute to the inflammatory HNC microenvironment as drivers of this process. More emphasis now is being placed on exploring the roles of the different immune cells in cancer control, tumorigenesis and metastasis. Myeloid cells are the most numerous immune cell types in the body, and they are actively recruited and reprogrammed by tumor cells to behave in a variety of ways. These cells are remarkably diverse in phenotype and function, and the part they play in tumor spread greatly differs based on the cell type. This review will focus on summarizing the roles of macrophages, neutrophils, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs) in driving HNC metastasis by examining the current knowledge base and offering potential new routes through which to target and treat this deadly process.
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OBJECTIVE: To determine differences in post-treatment QoL across treatment settings in patients receiving adjuvant radiation therapy for head and neck squamous cell carcinoma (HNSCC). METHODS: This was a prospective observational cohort study of patients with HNSCC initially evaluated in a head and neck surgical oncologic and reconstructive clinic at an academic medical center (AMC). Participants were enrolled prior to treatment in a prospective registry collecting demographic, social, and clinical data. Physical and social-emotional QoL (phys-QoL and soc-QoL, respectively) was measured using the University of Washington-QoL questionnaire at pre-treatment and post-treatment visits. RESULTS: A cohort of 177 patients, primarily male and White with an average age of 61.2 ± 11.2 years, met inclusion criteria. Most patients presented with oral cavity tumors (n = 132, 74.6%), had non-HPV-mediated disease (n = 97, 61.8%), and were classified as Stage IVa (n = 72, 42.8%). After controlling for covariates, patients treated at community medical centers (CMCs) reported a 7.15-point lower phys-QoL compared with those treated at AMCs (95% CI: -13.96 to -0.35, p = 0.040) up to 12 months post-treatment. Additionally, patients who were treated at CMCs had a 5.77-point (-11.86-0.31, p = 0.063) lower soc-QoL score compared with those treated at an AMC, which was not statistically significant. CONCLUSION: This study revealed that HNSCC patients treated with radiation at AMCs reported significantly greater phys-QoL in their first-year post-treatment compared to those treated at CMCs, but soc-QoL did not differ significantly. Further observational studies are needed to explore potential factors, including treatment planning and cancer resource engagement, behind disparities between AMCs and CMCs. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3645-3655, 2024.
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Neoplasias de Cabeça e Pescoço , Qualidade de Vida , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Prospectivos , Radioterapia Adjuvante , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/psicologia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/psicologia , Idoso , Inquéritos e QuestionáriosRESUMO
Introduction: The transmission dynamics of the recent mpox outbreak highlights the lack of infrastructure available to rapidly respond to novel STI outbreaks, of which Asia and Oceania remains particularly susceptible. Here, we simulate outbreaks in this setting and propose the use of pre-emptive vaccination within the men who have sex with men (MSM) community before the arrival and establishment of the virus. Materials and methods: Using data driven heterogeneous sexual contact networks, we simulated outbreaks of mpox in Singapore, Hong Kong, and Sydney. An individual based SEIR compartmental model was used to simulate epidemic trajectories and the impact of different vaccination uptakes was assessed in their ability to avert or suppress outbreaks upon the arrival of mpox within the MSM populations. Results: The highly dense sexual networks of Singapore and Sydney experience rapid outbreaks, with infection peaks occurring at day 41 and 23 respectively, compared to Hong Kong which occurs at day 77. Across the simulations with no vaccination, 68.2%-89.7% of the MSM community will become infected with mpox across the different cities, over a simulation period of 1 year. By implementing vaccination strategies, the infection rate across the cities can be reduced to as low as 3.1% of the population (range: 3.1%-82.2%) depending on the implementation and uptake of the vaccine. Vaccination is also extremely effective in slowing the start of the epidemic, delaying the epidemic peak by 36-50 days in Hong Kong, or even preventing the outbreak of mpox. Discussion: With extremely dense and well-connected sexual contact networks, where 65.2%-83.2% of the population are connected to a super-spreader in the different contact networks, pre-emptive or immediate vaccination upon identification of the first case is strongly recommended to help better manage the outbreak of mpox and prevent potential straining of healthcare systems.
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BACKGROUND: Transmission intensity for mosquito-borne diseases are highly heterogenous and multi-factorial. Understanding risk factors associated to disease transmission allow the optimization of vector control. This study sets out to understand and compare the combined anthropogenic and environmental risk factors of four major mosquito-borne diseases, dengue, malaria, chikungunya and Japanese encephalitis in Thailand. METHODS: An integrated analysis of mosquito-borne diseases, meteorological and ambient air pollutants of 76 provinces of Thailand was conducted over 2003-2021. We explored the use of generalized linear models and generalized additive models to consider both linear and non-linear associations between meteorological factors, ambient air pollutants and mosquito-borne disease incidence. Different assumptions on spatio-temporal dependence and nonlinearity were considered through province-specific and panel models, as well as different spline functions. Disease-specific model evidence was assessed to select best-fit models for epidemiological inference downstream. RESULTS: Analyses indicated several findings which can be generally applied to all diseases explored: (1) higher AH above mean values was positively associated with disease case counts (2) higher total precipitation above mean values was positively associated with disease case counts (3) extremely high temperatures were negatively associated with disease case counts (4) higher SO2 and PM2.5 surface concentrations were negatively associated with disease case counts. However, the relationships between disease and RH, non-extreme temperatures and CO surface concentration were more mixed, with directions of associations changing across the different diseases considered. CONCLUSIONS: This study found protective and enhancing effects of meteorological and ambient air pollutant factors on mosquito-borne diseases burdens in Thailand. Further studies should employ these factors to understand and predict risk factors associated with mosquito-borne disease transmission.
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Poluentes Atmosféricos , Poluição do Ar , Poluentes Ambientais , Doenças Transmitidas por Mosquitos , Animais , Humanos , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Poluentes Ambientais/análise , Tailândia/epidemiologia , TemperaturaRESUMO
OBJECTIVES: Understand the prognostic impact of perineural invasion (PNI) in early-stage oral cavity squamous cell carcinoma (OCSCC). Assess the influence of adjuvant radiotherapy on outcomes of patients with PNI-positive early-stage OCSCC. MATERIALS AND METHODS: Retrospective seven-institution cohort study including patients with pathologic T1-2 N0-1 OCSCC who underwent primary surgery with negative margins. Outcomes included disease-free survival (DFS) and locoregional control (LRC). Cox proportional hazards models were used to evaluate oncologic outcomes. Interaction terms were introduced to assess relationships between PNI and adjuvant radiotherapy. RESULTS: Among 557 patients (mean (SD) age 61.0 (13.9), 47.2% female, 66.6% pathologic T1, 93.5% pathologic N0), 93 had PNI-positive tumors, among which 87.1% underwent neck dissection and 39.6% received radiotherapy. On multivariable analysis, PNI was associated with lower DFS and LRC. Adjuvant radiotherapy was not associated with improved outcomes on multivariable analysis of the entire cohort. However, among patients with PNI-positive tumors, adjuvant radiotherapy significantly decreased hazard for DFS. CONCLUSION: Among patients with low-risk, early-stage OCSCC, PNI was associated with worse DFS and LRC. In patients with PNI-positive tumors, adjuvant radiotherapy lowered hazard for DFS on multivariable analysis. These data support using adjuvant radiotherapy for patients with early-stage OCSCC with PNI.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estudos de Coortes , Estudos Retrospectivos , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Prognóstico , Radioterapia Adjuvante , Neoplasias Bucais/radioterapia , Neoplasias Bucais/cirurgia , Neoplasias de Cabeça e Pescoço/patologia , Invasividade Neoplásica/patologia , Estadiamento de NeoplasiasRESUMO
Importance: Timely initiation of postoperative radiation therapy (PORT) is associated with reduced recurrence rates and improved overall survival in patients with head and neck squamous cell carcinoma (HNSCC). Measurement of the association of social-ecological variables with PORT delays is lacking. Objective: To assess individual and community-level factors associated with PORT delay among patients with HNSCC. Design, Setting, and Participants: This prospective cohort study carried out between September 2018 and June 2022 included adults with untreated HNSCC who were enrolled in a prospective registry at a single academic tertiary medical center. Demographic information and validated self-reported measures of health literacy were obtained at baseline visits. Clinical data were recorded, and participant addresses were used to calculate the area deprivation index (ADI), a measure of community-level social vulnerability. Participants receiving primary surgery and PORT were analyzed. Univariable and multivariable regression analysis was performed to identify risk factors for PORT delays. Exposures: Surgical treatment and PORT. Main Outcomes and Measures: The primary outcome was PORT initiation delay (>42 days from surgery). Risk of PORT initiation delay was evaluated using individual-level (demographic, health literacy, and clinical data) and community-level information (ADI and rural-urban continuum codes). Results: Of 171 patients, 104 patients (60.8%) had PORT delays. Mean (SD) age of participants was 61.0 (11.2) years, 161 were White (94.2%), and 105 were men (61.4%). Insurance was employer-based or public among 65 (38.5%) and 75 (44.4%) participants, respectively. Mean (SD) ADI (national percentile) was 60.2 (24.4), and 71 (41.8%) resided in rural communities. Tumor sites were most commonly oral cavity (123 [71.9%]), with 108 (63.5%) classified as stage 4 at presentation. On multivariable analysis, a model incorporating individual-level factors with health literacy in addition to community-level factors was most predictive of PORT delay (AOC= 0.78; R2, 0.18). Conclusions and Relevance: This cohort study provides a more comprehensive assessment of predictors of PORT delays that include health literacy and community-level measures. Predictive models that incorporate multilevel measures outperform models with individual-level factors alone and may guide precise interventions to decrease PORT delay for at-risk patients with HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Masculino , Adulto , Humanos , Pessoa de Meia-Idade , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgiaRESUMO
OBJECTIVE: In patients with head and neck squamous cell carcinoma (HNSCC), initiating postoperative radiotherapy (PORT) greater than 42 days after surgery is associated with a higher risk of poor survival outcomes. Social support has been shown to modulate behaviors related to care-seeking and treatment adherence. In this study, we sought to determine the relationship between social support metrics and PORT delays. STUDY DESIGN: Prospective cohort study. SETTING: Single tertiary medical center. METHODS: Patients with HNSCC who underwent primary surgical excision requiring PORT were prospectively enrolled. Patient-perceived social support metrics were assessed using the Medical Outcomes Study Social Support Survey (MOS-SSS) at initial presurgical evaluation. Associations with PORT delays were evaluated via univariable and multivariable logistic regression analysis. RESULTS: A total of 111 patients met the inclusion criteria for the study. An additional 28 patients were recommended to receive PORT but did not initiate treatment and were included for secondary analysis. All four subscales of the MOS-SSS (positive social interaction, affectionate support, tangible support, and emotional/informational support) were significantly associated with PORT initiation delays on univariable analysis. On multivariable analysis, the overall MOS-SSS score (odds ratio [OR] 2.08, 1.15-4.35, p = .028) was significantly associated with PORT initiation delays. On secondary analysis, lower tangible support was associated with a lack of PORT initiation (OR 1.63, 1.05-2.54, p = .028). CONCLUSION: Social support metrics were significantly associated with PORT delays, which may help promote tighter scheduling and closer monitoring of high-risk patients.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Radioterapia Adjuvante , Carcinoma de Células Escamosas/patologia , Estudos Prospectivos , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Apoio Social , Estudos RetrospectivosRESUMO
PURPOSE: To provide evidence-based recommendations for practicing physicians and other health care providers on immunotherapy and biomarker testing for head and neck cancers. METHODS: ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radiology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and locoregional control. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 28 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: When possible, evidence-based recommendations were developed to address biomarker testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence.Additional information is available at www.asco.org/head-neck-cancer-guidelines.
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Neoplasias de Cabeça e Pescoço , Humanos , Biomarcadores , Imunoterapia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate the effect of histopathologic skin invasion on 2- and 5-year disease-free survival (DFS) and overall survival (OS) in patients treated with primary surgery for locally advanced oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: A retrospective case-control study was performed comparing previously untreated patients with pT4a OCSCC with and without skin invasion. SETTING: Academic medical center. METHODS: Propensity score-matched cohorts were derived by age, sex, surgical margins, pathologic N classification, adjuvant treatment, and primary tumor site. The Kaplan-Meier method was used to evaluate 2- and 5-year OS and DFS, which were compared between cohorts via the log rank (Mantel-Cox) test statistic. RESULTS: Overall 25 patients were identified to have pathologic skin invasion, and 50 were selected for the matched control group. OS was significantly lower for patients with skin invasion as compared with controls at 2 years (30.8% vs 53.3%, P = .018) and 5 years (16.6% vs 42.2%, P = .01). DFS was significantly lower for patients with skin invasion vs controls at 2 years (23.7% vs 47.7, P = .037) and 5 years (15.8% vs 41.4%, P = .024). CONCLUSION: Histopathologic skin invasion in OCSCC is associated with dismal prognosis in patients who underwent primary surgical treatment. OS outcomes for patients with skin invasion are comparable to survival of patients with recurrent/metastatic disease and T4N2 disease.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Estudos Retrospectivos , Estudos de Casos e Controles , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologiaRESUMO
INTRODUCTION: Standard of care for radiosensitization in head and neck squamous cell carcinoma (HNSCC) is concurrent chemoradiotherapy (CCRT) with high-dose cisplatin. The optimal chemoradiation regimen for patients medically unfit for cisplatin is unclear. We compared our experience with concurrent cetuximab (CTX) versus other cytotoxic non-cisplatin agents. METHODS: We reviewed 53 patients between 2011 and 2017 with HNSCC treated with CCRT ineligible for cisplatin. Chemotherapy and radiotherapy treatment tolerance was evaluated in those receiving CTX versus non-CTX chemotherapy (NCC). Of the NCC regimens, the majority were carboplatin/paclitaxel and were dosed at an area under the curve (AUC) of 2 and 45-50 mg/m2, respectively. Standard radiation dosing was 70 Gray (Gy) in the definitive setting and 60-66 Gy in the postoperative setting. Patient characteristics and treatment toxicities were evaluated using categorical methods. RESULTS: Patients were well balanced overall including differences between performance status and the comorbidity score. NCC patients experienced more radiation treatment breaks (52.4% vs. 21.9%, p = 0.022), radiation delays >1 week (33.3% vs. 3.1%, p < 0.01), and chemotherapy dose-limiting toxicity (61.9% vs. 28.1%, p = 0.015) compared to CTX patients. Nutritional dependence on a PEG tube was more likely in the NCC cohort (52.4% vs. 22.6%, p = 0.027). CONCLUSION: Our results suggest decreased treatment tolerance in non-cisplatin cytotoxic chemotherapy compared to cetuximab. Further prospective study is needed to clarify optimal chemotherapy in patients unable to receive cisplatin.
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Antineoplásicos , Cetuximab , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Antineoplásicos/efeitos adversos , Cetuximab/efeitos adversos , Quimiorradioterapia , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Resultado do TratamentoRESUMO
We report a microfluidic assay to select active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral particles (VPs), which were defined as intact particles with an accessible angiotensin-converting enzyme 2 receptor binding domain (RBD) on the spike (S) protein, from clinical samples. Affinity selection of SARS-CoV-2 particles was carried out using injection molded microfluidic chips, which allow for high-scale production to accommodate large-scale screening. The microfluidic contained a surface-bound aptamer directed against the virus's S protein RBD to affinity select SARS-CoV-2 VPs. Following selection (~94% recovery), the VPs were released from the chip's surface using a blue light light-emitting diode (89% efficiency). Selected SARS-CoV-2 VP enumeration was carried out using reverse transcription quantitative polymerase chain reaction. The VP selection assay successfully identified healthy donors (clinical specificity = 100%) and 19 of 20 patients with coronavirus disease 2019 (COVID-19) (95% sensitivity). In 15 patients with COVID-19, the presence of active SARS-CoV-2 VPs was found. The chip can be reprogrammed for any VP or exosomes by simply changing the affinity agent.
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This study was performed to identify treatment related toxicities in older adults undergoing concurrent chemoradiotherapy for head and neck cancer and nutritional and skeletal muscle measures that might identify frailty. Imaging analysis was done with the following skeletal muscle measurements: skeletal muscle index (SMI), skeletal muscle density (SMD), and skeletal muscle gauge (SMG). Patients were dichotomized by age into younger (<70 years old, 221 patients) and older age groups (≥70 years old, 51 patients). Low SMI was more common in older patients (86.7%) compared to younger patients (51.7%, p < 0.01), as were low SMD (57.8% vs. 37.3%, p = 0.012) and low SMG (76.1% vs. 44.2%, p < 0.01), despite having similar BMIs (27.3 kg/m2 versus 27.7 kg/m2, p = 0.71). Older patients were significantly more likely to experience chemotherapy toxicity than younger patients (54.9% versus 32.3%, p < 0.01). On multivariate analysis age (p < 0.01), current smoking status (p < 0.01), and low SMI (p < 0.01) remained as significant predictors for missed chemotherapy cycles or discontinuation. Older patients were more likely to require ≥5-day radiation breaks than younger patients (27.5% versus 8.6%, p < 0.01). On multivariate analysis, age (p < 0.01), low albumin status (p = 0.03), and low SMI (p = 0.04) were identified as predictors of prolonged radiation treatment breaks. Based on the results of our study, sarcopenia may be used as an additional marker for frailty alongside traditional performance status scales.
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PURPOSE: Compared to CONV-RT (with conventional dose rate), FLASH-RT (with ultra-high dose rate) can provide biological dose sparing for organs-at-risk (OARs) via the so-called FLASH effect, in addition to physical dose sparing. However, the FLASH effect only occurs, when both dose and dose rate meet certain minimum thresholds. This work will develop a simultaneous dose and dose rate optimization (SDDRO) method accounting for both FLASH dose and dose rate constraints during treatment planning for pencil-beam-scanning proton therapy. METHODS: SDDRO optimizes the FLASH effect (specific to FLASH-RT) as well as the dose distribution (similar to CONV-RT). The nonlinear dose rate constraint is linearized, and the reformulated optimization problem is efficiently solved via iterative convex relaxation powered by alternating direction method of multipliers. To resolve and quantify the generic tradeoff of FLASH-RT between FLASH and dose optimization, we propose the use of FLASH effective dose based on dose modifying factor (DMF) owing to the FLASH effect. RESULTS: FLASH-RT via transmission beams (TB) (IMPT-TB or SDDRO) and CONV-RT via Bragg peaks (BP) (IMPT-BP) were evaluated for clinical prostate, lung, head-and-neck (HN), and brain cases. Despite the use of TB, which is generally suboptimal to BP for normal tissue sparing, FLASH-RT via SDDRO considerably reduced FLASH effective dose for high-dose OAR adjacent to the target. For example, in the lung SBRT case, the max esophageal dose constraint 27 Gy was only met by SDDRO (24.8 Gy), compared to IMPT-BP (35.3 Gy) or IMPT-TB (36.6 Gy); in the brain SRS case, the brain constraint V12Gy≤15cc was also only met by SDDRO (13.7cc), compared to IMPT-BP (43.9cc) or IMPT-TB (18.4cc). In addition, SDDRO substantially improved the FLASH coverage from IMPT-TB, e.g., an increase from 37.2% to 67.1% for lung, from 39.1% to 58.3% for prostate, from 65.4% to 82.1% for HN, from 50.8% to 73.3% for the brain. CONCLUSIONS: Both FLASH dose and dose rate constraints are incorporated into SDDRO for FLASH-RT that jointly optimizes the FLASH effect and physical dose distribution. FLASH effective dose via FLASH DMF is introduced to reconcile the tradeoff between physical dose sparing and FLASH sparing, and quantify the net effective gain from CONV-RT to FLASH-RT.
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Terapia com Prótons , Radioterapia de Intensidade Modulada , Humanos , Masculino , Órgãos em Risco , Terapia com Prótons/métodos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodosRESUMO
Cancer and the immune system share an intimate relationship. Chronic inflammation increases the risk of cancer occurrence and can also drive inflammatory mediators into the tumor microenvironment enhancing tumor growth and survival. The p38 MAPK pathway is activated both acutely and chronically by stress, inflammatory chemokines, chronic inflammatory conditions, and cancer. These properties have led to extensive efforts to find effective drugs targeting p38, which have been unsuccessful. The immediate downstream serine/threonine kinase and substrate of p38 MAPK, mitogen-activated-protein-kinase-activated-protein-kinase-2 (MK2) protects cells against stressors by regulating the DNA damage response, transcription, protein and messenger RNA stability, and motility. The phosphorylation of downstream substrates by MK2 increases inflammatory cytokine production, drives an immune response, and contributes to wound healing. By binding directly to p38 MAPK, MK2 is responsible for the export of p38 MAPK from the nucleus which gives MK2 properties that make it unique among the large number of p38 MAPK substrates. Many of the substrates of both p38 MAPK and MK2 are separated between the cytosol and nucleus and interfering with MK2 and altering this intracellular translocation has implications for the actions of both p38 MAPK and MK2. The inhibition of MK2 has shown promise in combination with both chemotherapy and radiotherapy as a method for controlling cancer growth and metastasis in a variety of cancers. Whereas the current data are encouraging the field requires the development of selective and well tolerated drugs to target MK2 and a better understanding of its effects for effective clinical use.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias , Proteínas Serina-Treonina Quinases/metabolismo , Sobrevivência Celular , Humanos , Sistema de Sinalização das MAP Quinases , Microambiente Tumoral , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Lung is the most common site of distant metastasis for patients with head and neck squamous cell carcinoma (HNSCC). However, differentiating second primary lung cancers from metastasis may be difficult for p16 negative HNSCC. CASE: We describe a case of oral cavity squamous cell carcinoma (SCC) who was found to have lung nodule and hilar lymphadenopathy (LAD) after surgery and radiation therapy. Hilar node was consistent with SCC however, it was difficult to differentiate second primary lung cancer and metastasis from oral cavity SCC. Next-generation sequencing was done for the primary oral cavity and the hilar node. Both samples had the same type of TP53 mutation and variants of unknown significance suggesting metastatic HNSCC. He was treated with a chemotherapy regimen for metastatic HNSCC. CONCLUSION: Molecular studies can help to differentiate metastasis from second primary lung cancers for p16 negative HNSCC.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Bucais/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diagnóstico Diferencial , Humanos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Boca/patologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/patologia , Mutação , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Proteína Supressora de Tumor p53/genéticaRESUMO
IMPORTANCE: Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases. OBJECTIVE: To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other. DESIGN, SETTING, AND PARTICIPANTS: This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non-small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019. INTERVENTIONS: The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP). MAIN OUTCOMES AND MEASURES: The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated. RESULTS: A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non-small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients. CONCLUSIONS AND RELEVANCE: This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute-sponsored trials (NRG-BR002, NRG-LU002). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02206334.